The natriuresis that follows ingestion of a solute load is more rapid than the natriuresis that occurs when an equivalent solute load is given intravenously, due to the operation of an entero-renal endocrine axis. Efforts to identify the hormonal mediator(s) of this axis have recently focused on uroguanylin (UGnn), a 17 amino acid peptide that activates guanylate cyclase-C (GC-C), a member of the ligand-activated family of receptor/guanylate cyclases. Key features of UGnn include the following: (1) its precursor (proUGn) is expressed primarily in the intestine, (2) UGnn circulates in the plasma, (3) infusion of exogenous UGnn induces renal natriuresis and diuresis, and (4) ablation of the uroguanylin gene elevates blood pressure and markedly decreases the rate of excretion of orally-delivered salt. However, two observations argue against a role for UGnn in salt homeostasis. (1) UGnn is a relatively ineffective natriuretic agent, inducing small (2 - 4-fold) urinary responses, and those only at supra-normal concentrations. (2) GC-C, the only known receptor for UGnn, is barely expressed in the kidney. Furthermore, GC-C knockout animals lack the elevated blood pressure seen in mice after ablation of the uroguanylin gene. Thus, although an intact uroguanylin gene is necessary for efficient excretion of oral salt, the known properties of UGnn and GC-C are inadequate to account for the phenotype of uroguanylin knockout animals. The preliminary data presented in this application provide an explanation for this paradox. We have found that intravenous infusion of proUGn into anesthetized rats provokes dramatic (30-fold) increases in renal Na excretion-though, like others, we detect only small responses mediated by GC-C. In addition, using a newly-developed immunoassay for proUGn, we have shown that levels of endogenous proUGn in plasma respond to dietary salt intake. Thus, we propose that either proUGn itself, or a metabolite derived from it (but distinct from UGnn), is the true natriuretic link between the gut and the kidney. Experiments described in our application will test and extend this hypothesis, and may suggest uses for proUGn in the diagnosis or treatment of diseases in which salt and/or fluid homeostasis is deranged.